The long-term goal of this project is to elucidate the mechanisms by which erbB2 regulates mammalian development. The erbB signaling network has been established as a key regulator of multiple developmental and physiological processes, including synaptic development. ErbB2 is a member of the epidermal growth factor receptor (EGFR or erbB1) family that also includes erbB3 and erbB4. Receptor heterodimerization of erbB2, erbB3 and erbB4 is essential for NRG signaling. One of central questions in synaptic development is how positive and negative signals to sculpt both presynaptic terminals and postsynaptic apparatus to ensure that each postsynaptic apparatus is closely apposed by a specialized nerve terminal. Those that are not apposed are dispersed by the negative signals. NRG1-ErbB receptor signaling has emerged as an essential pathway to modulate synaptic differentiation. There are at least three issues with which we are confronted to understand the role of erbB2 and other erbB receptors in mammalian development. First, erbB2 is expressed in multiple cell types, which are essential for the proper development and function of several organs and neuronal structures. ErbB2 may play distinct functions in each of cell types. Second, the distinct physiological roles of erbB2 are based on the timing and patterns of erbB2 protein expression throughout embryonic and postnatal development. Third, there is functional redundancy among erbB receptors, depending on the compliment of the erbB receptors and cellular context. Furthermore, recently results suggest that Cdk5 and its target substrate intermediate filament protein nestin both of which are co-localized at synaptic sites, are the downstream molecules of the NRG1-erbB receptor pathway to regulate synaptic differentiation. In the present proposal, we will combine conditional mutation mouse genetics, anatomical, cellular, molecular, and biochemical approaches to elucidate the role of erbB2 and erbB4 in neural development. Aim 1 is to determine the role of the erbB2/erbB4->-Cdk5 pathway in NRG1-regulated synaptic development. Aim 2 is to determine the role of nestin in NMJ development and in NRG 1-induced dispersion of AChR clusters. Aim 3 is to elucidate the mechanisms by which nestin modulates the stability of AChR clusters by NRG1 Public health relevance. Further understanding of the cellular and molecular mechanisms underlying NRG signaling mediated by the erbB receptors not only advances our knowledge of the development of several organs, neural and neuroendocine systems but may also provide insights into the biology of human diseases, including neurodegenerative diseases, sensory and motor neuropathies, cardiac diseases and breast cancer. This signaling pathway has been recently implicated in human disorders such as schizophrenia.